ACW Lee, KW Wong, SC Szeto, KS Tong, KT So

Abstract

A 3-year-old Chinese boy with congenital factor VII deficiency presented with recurrent gastrointestinal bleeding, epistaxis, hemarthrosis and soft tissue bleeding. The hemorrhagic symptoms were ameliorated with infusions of fresh frozen plasma, but it was complicated by hyperalbuminemia, hypergammaglobulinemia and hypertension. When the treatment was switched to plasma-derived factor VII concentrate, hemostatic control improved with resolution of the complications, Although factor VII concentrate is expensive, it may be the preferred treatment in the patient with severe factor VII deficiency in terms of clinical efficacy and cost effectiveness.

Introduction

Congenital factor VII deficiency is an uncommon disorder with an estimated prevalence of 1 in 500000 population. It is transmitted in an autosomal recessive inheritance and heterozygotes are usually asymptomatic. In the laboratory, it is readily distinguished from other bleeding disorders by a prolonged prothrombin time with a normal partial thromboplastin time and, platelet count. The clinical manifestations of factor VII deficiency are extremely variable. At the mild end of the spectrum patients can be asymptomatic and the condition may only be discovered incidentally, At the severe end patients may resemble classic hemophilia with soft tissue and intra-articular bleedings. The clinical severity, however, cannot be accurately predicted from the measured plasma factor VII levels.¹

The introduction of factor VII concentrate in the last decade provides a safe and effective alternative to fresh frozen plasma in the treatment of bleeding secondary to factor VII deficiency.² Either plasma-derived factor VII or recombinant activated factor VII is available for therapeutic use, but both are expensive. Against the background of variable clinical severity, it can be difficult to choose the most appropriate form of treatment on the account of cost effectiveness. We report a case of severe factor VII deficiency who has been successfully managed with factor VII concentrate.

Case Report

A Chinese boy first presented at 8 months old with fresh blood in stool. There was no diarrhea or superficial signs of bleeding. His parents were first cousins and his three elder sisters were enjoying good health. At 3 years 3 months old, he presented with febrile convulsion and an upper respiratory infection. He also complained of a coffee-ground vomitus and tarry stool. Swelling of the right knee had been noted for a couple of days. These symptoms subsided spontaneously after admission. An investigation into the bleeding tendency was performed. The complete blood counts showed a hemoglobin of 10.3 g/dl and a platelet count of 437 x 10⁹/l. The serum biochemistries and transaminases were normal. The prothrombin time was markedly prolonged at 56.4 s (INR > 4.5) but the activated partial thromboplastin time was normal at 33.5s. The factor VII level was 0.01 iu/ml. The corresponding levels were 0.53 and 0.43 iu/ml for his father and mother respectively.

In the subsequent year, he was admitted repeatedly for treatment of bleeding. These included upper gastrointestinal bleeding, epistaxis, gum bleeding, hematuria, subconjunctival hemorrhage, hemarthroses of the left metatarsophalangeal joints, right knee and right elbow and soft tissue bleeding involving the neck region and dorsum of left foot. All these bleeding episodes were treated with fresh frozen plasma, with a maximum daily dose of two units every 12 hours. The severity of bleeding was reflected by the massive consumption of blood products. During this period, he had been transfused with 301 units of fresh frozen plasma and six units of packed red cells. The latter was given on five occasions when his hemoglobin dropped to less than 7.0 g/dl. Despite this persistent oozing from the gum was still evident prior to each infusion of fresh frozen plasma. The addition of tranexamic acid did not produce any beneficial effect.

At the same time, he developed hyperalbuminemia (highest serum albumin 64 g/l), hypergammaglobulinemia (IgG 26.6 g/l, IgA 5.25 g/l, 1gM 3.72 g/l), massive proteinuria (21.4 g/day) and hypertension requiring treatment with hydralazine. Within the first year of diagnosis, he had been staying in the hospital for 296 days.

Treatment with factor VII concentrate

A trial of treatment with plasma-derived factor VII concentrate was carried out for one week. At a dose of 500 iu factor VII (31 iu/kg) every 12 hours, the mucosal bleeding stopped and there was no further bleeding. Factor VII levels were assayed at the first dose and the corresponding levels at 0, 10 and 240 minutes were 0.03, 0.75 and 0.47 iu/ml, respectively. This suggests an in vivo recovery of 2.3% per iu per kilogram body weight, which is similar to the reported values.³

The child was initially put on a regular treatment with factor VII concentrate at a dose of 500 iu per day. This was gradually tapered to 500 iu two times weekly, with supplementary doses whenever the child bled. With the cessation of fresh frozen plasma treatment, the hypertension and proteinuria resolved, and the serum albumin returned to normal levels. The prophylactic factor VII concentrate was stopped after five months, and further treatment was continued whenever he was symptomatic.

Discussion

Congenital factor VII deficiency is a rare disorder. The gene coding for factor VII has been localized to chromosome 13q34. There may be a disparity between the reduction of activity and antigen levels such that factor VII deficiency can be classified into cross-reacting material negative (type 1) or positive (type 2). The genetics and molecular pathology of factor VII deficiency have been reviewed.⁴

The clinical manifestation of factor VII deficiency can be extremely variable among different patients. Newborns with severe factor VII deficiency may have a tendency to bleed intracranially,⁵ even after an apparently non-traumatic delivery.⁶ And the severity of bleeding does not correlate with the degree of measured deficiency.¹ The present case represents one of those patients at the severe end of the spectrum, whose symptoms and signs resemble a moderate to severe case of classic hemophilia. The other case of factor VII deficiency under our case is a 7-year-old girl who only presents with intermittent episodes of gum bleeding. Her symptom responds well to short courses of tranexamic acid alone despite a measured factor VII level of 1%.

Bleeding associated with factor VII deficiency is traditionally treated with fresh frozen plasma. Effective hemostasis can be achieved with short courses of therapy in the pen-operative periods.⁷ When regular treatment is necessary, however, this may be complicated by fluid overload⁸ and overdose with other plasma components. Because of the short half-life of factor VII (about 4-6 hours), a large amount of fresh frozen plasma will be needed in a patient with severe bleeding. The present report demonstrates the consequences of the traditional approach under such circumstances. Although cardiovascular decompensation can be avoided with careful fluid management, the excessive plasma infusion results in hyperalbuminemia and hypergammaglobulinemia. The excessive plasma proteins then cause hypertension and heavy proteinuria. Fortunately, these were reversed shortly after the institution of therapy with factor VII concentrates and no significant consequences were observed.

There are currently two available forms of factor VII concentrates. The one that we are using is a plasma-derived product that has been subjected to viral inactivation procedures. Its clinical efficacy and pharmacological properties have been shown previously in selected cases of factor VII deficiency.⁹ The other product is an activated factor VII manufactured by recombinant DNA technique and successful clinical use has also been reported.¹⁰

The current cost of a single dose (500 iu per vial) of plasma-derived factor VII concentrate in our locality is HK$ 4,800. However, given an average in-patient bed-day cost of $3,370,¹¹ hospitalization alone had cost almost a million while the child was on plasma replacement treatment. After the use of factor VII concentrate, the child is managed as an out-patient and he only requires treatment once every two weeks. The saving in hospital care is obvious. Schooling in kindergarten was resumed. Thus, treatment with factor VII concentrate in patients with severe factor VII deficiency could be cost effective and allow the patient a better quality of life.

Plasma derived product must be used with caution. The potential infectious complications associated with factor concentrates are well known. Factor VII deficiency does not protect against thrombotic complications, and arterial thrombosis has been reported after factor VII concentrate infusion.¹² Whether this is a mere coincidence or treatment associated as in the case of prothrombin complex' remains unclear.

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